Background We previously demonstrated that exposure to environmental tobacco smoke (ETS) increases the development of atherosclerosis in lipid-fed rabbits. Clinical studies have suggested a protective effect of beta -blockers in smokers. Accordingly, we evaluated the effects of metoprolol in this animal model to see whether this beta -blocker would block the atherogenic effects of ETS.Methods and Results Thirty-two New Zealand White male rabbits on a 0.3% cholesterol diet were randomly divided into four groups: ETS-metoprolol (ETS-M), ETS-control (ETS-C), and non-ETS with metoprolol (NETS-M) and without metoprolol (NETS-C). The two metoprolol-treated groups received metoprolol at a dose of 0.4 mg x kg-1x h-1administered subcutaneously by an osmotic pump. Rabbits in the ETS groups were exposed to sidestream smoke from four Marlboro cigarettes per 15 minutes, 6 hours a day, for 10 weeks. Average air carbon monoxide (CO), nicotine, and total particulates (TP) in the exposure chambers were 67.2+-3.1 (SEM) ppm, 1133.7+-78.4 micrograms/m3, and 37.7+-3.0 mg/m3, respectively. Plasma nicotine was significantly higher in ETS-exposed rabbits than in nonexposed rabbits (7.1+-1.9 versus 0.5+-0.1 ng/mL, P<.01). Blood carbon monoxide hemoglobin (COHb) in the ETS-M group was significantly higher than that in the NETS-M group (4.0+-0.2% versus 1.3+-0.1%, P<.0001). The lipid lesions in the aorta and pulmonary artery were 57.2+-7.6% and 33.1+-6.4% (ETS-M), 62.8+-8.4% and 58.4+-6.1% (ETS-C), 38.7+-9.4% and 24.8+-7.7% (NETS-M), and 49.8+-8.7% and 32.7+-7.1% (NETS-C). There were significant differences in lipid deposits of the arteries between the controls and the ETS-exposed rabbits (37+-1% versus 53+-1%, P=.004) and between the controls and metoprolol-treated rabbits (51+-1% versus 38+-1%, P=.027). The benefit of metoprolol was independent of ETS exposure (ETS x metoprolol interaction, P=.595).Conclusions Exposure to ETS significantly accelerated and metoprolol decreased the development of atherosclerosis in lipid-fed rabbits, but there was no interaction between the effects of ETS exposure and metoprolol. Metoprolol did not protect against the effects of ETS on atherosclerosis, suggesting that the beta -adrenergic system is not the mechanism of ETS-induced atherosclerosis. (Circulation. 1994;89:2260-2265.)